tbuckley/cabot-search huggingface dataset:
Abstract 6786: NT-I7 as an adjuvant to DNA neoantigen vaccination enhances and prolongs neoantigen-specific anti-tumor immunity
Authors: Michael Y. Chen, Ina Chen, Suangson Supabphol, Alexandra A. Wolfarth, Sara F. Martinez, Byung Ha Lee, Lijin Li, Xiuli Zhang, Peter S. Goedgebuure, William E. Gillanders
Journal: Cancer Research (2023)

Abstract Background: IL-7 is an essential cytokine in the development and maintenance of antigen-specific T cells. NT-I7 (efineptakin alfa; NeoImmuneTech, Inc, Rockville, MD), is a long acting IL-7 composed of recombinant human IL-7 (rhIL-7) fused to a hybrid Fc antibody platform that has significantly improved in vivo stability and half-life compared to rhIL-7. DNA cancer neoantigen vaccines are a promising personalized cancer immunotherapy capable of generating strong anti-tumor immunity, but limited by a short-lived neoantigen-specific T cell response. We hypothesize NT-I7 as an adjuvant to a DNA neoantigen vaccine will enhance the magnitude and duration of neoantigen-specific anti-tumor immunity. Methods: C57BL/6 mice were vaccinated with DNA vaccine encoding neoantigens present in E0771 murine breast cancer model on days 0, 3, and 6. NT-I7 (5 mg/kg) was administered intravenously on day 4 or 13 during T cell expansion or contraction phase respectively. Primary T cell responses to neoantigens were assessed by IFN-γ ELISPOT. Tumor protection was evaluated by inoculating mice with 5×105 E0771 cells subcutaneously after receiving DNA vaccine with or without NT-I7. Duration of neoantigen-specific CD8 T cell immunity was determined by in vivo CFSE killing assay. Results: NT-I7 administered during the T cell contraction phase following the DNA vaccine increases the magnitude of neoantigen-specific T cell responses on day 20 compared to DNA vaccine alone. DNA vaccination and NT-I7 alone prior to tumor inoculation confers partial protection against tumor growth compared to control while DNA + NT-I7 during contraction phase rejects 100% of tumors. Compared to DNA vaccine alone, DNA vaccine + NT-I7 during contraction phase induces greater neoantigen-specific killing on day 41 (34.6% vs. 11.97%, p=0.03). Conclusion: NT-I7 as an adjuvant to a DNA neoantigen vaccine increases the magnitude and duration of neoantigen-specific anti-tumor immunity in a murine model. Clinical application of NT-I7 may help overcome immunologic shortcomings of current neoantigen vaccines. Citation Format: Michael Y. Chen, Ina Chen, Suangson Supabphol, Alexandra A. Wolfarth, Sara F. Martinez, Byung Ha Lee, Lijin Li, Xiuli Zhang, Peter S. Goedgebuure, William E. Gillanders. NT-I7 as an adjuvant to DNA neoantigen vaccination enhances and prolongs neoantigen-specific anti-tumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6786.
Abstract 4309: Early apoptotic measurements of patient-derived organoids predict patient response to therapy
Authors: Kelley E. McQueeney, Patrick Bhola, Sarah J. Hill, Anthony Letai
Journal: Cancer Research (2023)

Abstract The use of imperfect models and ex vivo culture systems to try to predict patient drug response represents an enormous bottle neck in cancer treatment. Nonetheless, determining how effective an approved drug will be for an individual cancer patient, as well as identifying novel compounds that may be beneficial to a specific population often requires the use of primary tumor cells. Patient-derived organoids represent an intermediate between primary tumor cells, whose limited supply may hinder reliable drug testing, and cell lines, which often do not reflect what happens in vivo. Herein, we describe the development of a novel assay platform, termed 3D-DBP (3D dynamic BH3 profiling), to detect early apoptotic measurements in ovarian cancer patient-derived organoids and present evidence that this method can be used to predict patient response to therapy. We have optimized the use of patient-derived organoids from 16 individual tumors in a microscopy-based imaging assay. We image the BH3 peptide-induced release of cytochrome c from mitochondria, which indicates permeabilization of the outer mitochondrial membrane, in intact organoids. The less cytochrome c retained in each organoid, the more primed that organoid is for apoptosis. By comparing results of drug-treated and untreated cells, we can identify drugs that cause a significant increase in apoptotic priming in organoids. In the 16 patient-derived organoids investigated this 3D DBP technique was an effective means of predicting patient response to carboplatin therapy. In summary, we have not only created a means of visualizing drug response in intact organoids, but also have demonstrated its clinical utility. Citation Format: Kelley E. McQueeney, Patrick Bhola, Sarah J. Hill, Anthony Letai. Early apoptotic measurements of patient-derived organoids predict patient response to therapy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4309.
Abstract 2844: BMP inhibition overcomes chemoresistance of prostate cancer
Authors: Jijun Hao, Chen Xie, Zhijun Wang, Yong Bar, Jose Aguilar, Austin Kyan, Li Zhing
Journal: Cancer Research (2023)

Abstract Chemoresistance is a major therapeutic challenge to prostate cancer and its underlying molecular mechanism is poorly understood. Previously, it has been suggested that bone morphogenetic protein (BMP) signaling is down-regulated during the prostate cancer progression from the early androgen-sensitive stage to the metastatic castration-resistant stage. However, no literature reports are available for BMP signaling in the more advanced-chemoresistant prostate cancer. In this study, we found the expression levels of the BMP type I receptor members, Activin-like kinase-2 (ALK2) and Activin-like kinase-3 (ALK3), were significantly higher in the chemoresistant prostate cancer cells than those in the chemosensitive prostate cancer cells. In addition, the phospho-Smad1/5/9 proteins, the pivotal intracellular effectors of the BMP signaling, were notably elevated in the chemoresistant prostate cancer cells over the chemosensitive prostate cancer cells, indicating that BMP signaling is highly activated in the chemoresistant prostate cancer cells. We also found that BMP signaling inhibition with either DMH1 or the knockdown of ALK2/ALK3 sensitized chemoresistant prostate cancer cells to the chemotherapy drug docetaxel in a dose dependent manner. Our further study indicates that DMH1 suppressed the migration and invasion of chemoresistant prostate cancer cells in vitro, and attenuated chemoresistant prostate tumor growth in the mouse xenograft model in vivo. In addition, we showed that DMH1 disrupted the sphere formation in DU145-TxR and PC3-TxR cells, suppressed the expression of marker genes of the cancer stem cells (CSCs), and inhibited the efflux activity of multidrug resistance P-glycoprotein (P-gp1). In conclusion, our study demonstrates that BMP signaling is associated with prostate cancer chemoresistance and BMP signaling inhibition effectively overcomes the cancer chemoresistance potentially through the disruption of CSCs’ stemness and P-gp1 efflux activity. Citation Format: Jijun Hao, Chen Xie, Zhijun Wang, Yong Bar, Jose Aguilar, Austin Kyan, Li Zhing. BMP inhibition overcomes chemoresistance of prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2844.
Abstract 1531: Human anti-CD40 agonistic antibodies with enhanced FcgR engagement activate immune cell and promote anti-tumor efficacy
Authors: Linya Wang, Tom Z. Yuan, Mouna Villalta, Zhen Han, Hansika Wadhwa, Kara Y. Chan, Marisa Yang, Tammy Htoy, Paul VanDyke, Carson Holliday, Hector Franco, Hoa Giang, Fumiko Axelrod, Aaron Sato
Journal: Cancer Research (2023)

Abstract Checkpoint inhibitors represent a major advance in cancer immunotherapy, and combinatorial immunotherapies with secondary drivers of anti-tumor immunity provide beneficial effects for patients that do not show a strong endogenous immune response. CD40 is a member of the TNF family of receptors that has been shown to play a crucial role in enhancing B cell and dendritic cell activity and fostering anti-tumor immune responses. Engagement of the inhibitory Fcg-receptor (FcgR) IIb is an absolute requirement for in vivo antitumor activity of agonistic anti-CD40 monoclonal antibodies, and Fc region mutant designs of anti-CD40 antibodies had been discovered to enhance FcgRIIb engagement. With Twist’s precision DNA writing technologies, we have created phage display VHH and scFv libraries with diversity greater than 1 × 1010 for optimal discovery. In this study, we performed high affinity binding of the antibodies by SPR and cell surface binding. The leads are reformatted on human IgG1, IgG4, and IgG1 mutant. The in vitro properties of the CD40 agonistic antibodies demonstrate enhanced FcgRIIb engagement by NFkB activation. B cell activation is also detected by upregulation of CD86 and IL6 secretion. In humanized hCD40 mice model, we observed the engineered anti-CD40 agonists enhance anti-tumor immune function in vivo. These studies suggest that our antibodies can be potential drug for cancer immunotherapy. Citation Format: Linya Wang, Tom Z. Yuan, Mouna Villalta, Zhen Han, Hansika Wadhwa, Kara Y. Chan, Marisa Yang, Tammy Htoy, Paul VanDyke, Carson Holliday, Hector Franco, Hoa Giang, Fumiko Axelrod, Aaron Sato. Human anti-CD40 agonistic antibodies with enhanced FcgR engagement activate immune cell and promote anti-tumor efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1531.
Abstract 953: Development of a predictive biomarker signature for the highly potent SIK3 inhibitor OMX-0407
Authors: Ilona-Petra Maser, Sonja Lacher, Vincent Piras, Barbara Kracher, Kai Zanziger, Murray Yule, Hannes Loferer, Stefan Bissinger
Journal: Cancer Research (2023)

Abstract Using the iOTarg genetic screening platform, salt-inducible kinase 3 (SIK3), a serine/threonine kinase of the AMP-activated protein kinase (AMPK) family was recently identified as a novel cell signaling modulator in cancer biology. OMX-0407, an orally available, single-digit nanomolar inhibitor of SIK3 was shown to inhibit tumor growth in a distinct panel of tumor models in vitro as well as in vivo by decreasing downstream pro-survival signaling of SIK3, enhancing caspase-mediated apoptosis and repolarizing the tumor microenvironment by decreasing regulatory T cells. In a comprehensive viability screening, more than 200 murine and human cancer cell lines and patient derived tumor models of different indications were used to identify a distinct subset of cancers highly sensitive towards OMX-0407. Representative for these tumors, OMX-0407 demonstrated dose-dependent anti-tumor efficacy in the renal cell carcinoma model RENCA, the squamous non-small cell lung cancer model (sqNSCLC) KLN205 and the murine colorectal tumor model MC38. With significantly prolonged overall survival of more than 60% tumor growth inhibition in all tumor models, OMX-0407 demonstrated equivalent or superior efficacy compared to anti-PD-1 monotherapy. In addition, OMX-0407 enhances the therapeutic potential of the standard of care chemotherapy in a broad range of human cancer cells and murine tumor models of sqNSCLC. Using comprehensive transcriptomics and proteomics analyses the selective activity profile of OMX-0407 on individual cancer cell lines and PDX models was used to identify and validate a predictive biomarker signature. With this gene signature, 84% of the selected cancer cells lines are correctly classified and would benefit from OMX-0407 therapy. The predictive biomarker will be evaluated in the clinical Phase I trial of OMX-0407 scheduled to start enrollment shortly. In summary, OMX-0407, a first-in-class oral SIK3 inhibitor, demonstrates potent monotherapy efficacy in tumor indications with high unmet medical need equal or superior to anti-PD-1 checkpoint blockade. By screening sensitive and non-sensitive tumor cell lines and PDX models, we identified a response-prediction biomarker signature. In upcoming clinical studies, this predictive biomarker signature will be evaluated for it’s potential to enrich for patients highly responsive to OMX-0407 therapy. Citation Format: Ilona-Petra Maser, Sonja Lacher, Vincent Piras, Barbara Kracher, Kai Zanziger, Murray Yule, Hannes Loferer, Stefan Bissinger. Development of a predictive biomarker signature for the highly potent SIK3 inhibitor OMX-0407 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 953.
Abstract 2349: Investigating the effect of ECM stiffness on macrophage-derived exosome secretion and PDAC organoid progression
Authors: Bayan Mahgoub, Weikun Xiao, Reginald Hill
Journal: Cancer Research (2023)

Abstract Pancreatic ductal adenocarcinoma (PDAC) has a 5-year survival rate of only 11%. Current treatments that mostly target the cancer cells themselves, have not been able to significantly improve survival rates, meaning there is an urgent need for novel therapies. PDAC is unique among solid tumors because it exhibits extensive desmoplasia that is characterized by an abundance of extracellular matrix (ECM) components. In recent years, an increasing body of work has shown that cancer tissue is stiffer than normal tissue by a factor of 3 or more. This change in ECM stiffness has been shown to play an important role in affecting cell to cell communication as well as cancer progression and chemoresistance. However, how ECM stiffness affects macrophages, an important immune component of the pancreatic tumor microenvironment (TME), and macrophage-derived exosome secretion is still understudied. Preliminary studies have shown that macrophages are highly sensitive to the mechanical environment. How cell-cell information transfer through exosomes may regulate this process in the PDAC tumor microenvironment (TME) needs to be explored. Elucidating these potential changes can provide us with insights on how stiffness affects therapeutic outcome in PDAC. Our previous studies utilizing a biomimetic model that allows us to tune stiffness, showed that increased stiffness resulted in significantly higher exosome secretion from fibroblasts. Based on this finding, we hypothesize that increasing stiffness will result in hypersecretion of macrophage-derived exosomes that increases the chemoresistance of PDAC. 2D culture of macrophages on varying stiffness plates was used to study these changes in vitro. We then examined how changes in ECM stiffness affected the function and polarization of tumor associated macrophages, as well as elucidating how exosome hypersecretion and uptake, regulate these “stiffness enhanced” macrophages’ ability to affect PDAC progression. Understanding how macrophage-derived exosome signaling changes due to ECM stiffness may provide us with insights needed to develop novel therapies. Citation Format: Bayan Mahgoub, Weikun Xiao, Reginald Hill. Investigating the effect of ECM stiffness on macrophage-derived exosome secretion and PDAC organoid progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2349.
Abstract 5909: Characterization of the lung cancer microbiome using whole genome sequencing
Authors: John McElderry, Tongwu Zhang, Jianxin Shi, Maria Teresa Landi
Journal: Cancer Research (2023)

Abstract Microbiome studies have been rapidly increasing over the last decade, providing valuable insights into the commensal bacterial contribution to human physiology and disease, including human cancer. Many studies have demonstrated the important roles of the microbiome in cancer progression, anti-tumor immunity, resistance to therapies, metastasis formation, and in some rare cases even cancer development through the production of genotoxins. However, relatively few studies have analyzed the lung cancer microbiome, and both its composition and role in cancer progression are largely unknown. To characterize the microbiome of tumor and matched normal lung tissues, we performed whole-genome sequencing (WGS) in 872 never smokers using the Kraken pipeline. At the phylum level, WGS analyses of tumor and normal samples showed predominantly Proteobacteria and Actinobacteria (58% and 32%, respectively). Notably, we found overall similar microbiome composition in tumor and normal lung tissue samples. At the genus level, Cutibacterium, Klebsiella, Pseudomonas, Sphingomonas, Staphylococcus, and Acinetobacter genera were among the most abundant bacteria in tumor and normal tissues, alike, and the genera Prevotella, Corynebacterium, and Streptococcus were more abundant in tumor samples compared to normal lung tissue. Comparison of alpha diversity at the genus level between tumors and normal samples showed no substantial difference. We are currently investigating whether the microbiome composition varies by lung tumor anatomical location, sex, histology, study subjects’ geographical location, and immune microenvironment. We will also investigate whether the tumor microbiome composition varies in relation to important genomic features, like cancer driver genes and mutational signatures. Finally, we have 16s rRNA seq data from 771 tumor and normal lung tissues from never smokers and we will compare bacterial microbiome composition and diversity based on WGS and 16s rRNA seq for the same samples. This study, based on the largest analysis of lung microbiome to date, is poised to provide important insights into the role of commensal microbiota in shaping lung tumor development and progression. Citation Format: John McElderry, Tongwu Zhang, Jianxin Shi, Maria Teresa Landi. Characterization of the lung cancer microbiome using whole genome sequencing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5909.
Abstract 326: Identification of novel substrates of the UBR5 E3 ubiquitin ligase in ovarian cancer
Authors: Scott T. Eblen, Jennifer R. Bethard, D Ralph Rogers, Abdelkader Daoud, Lalima K. Madan, Lauren E. Ball
Journal: Cancer Research (2023)

Abstract The ubiquitin proteasome system regulates the degradation of proteins in order to maintain cellular homeostasis, which is often disrupted in cancer cells. The UBR5 (Ubiquitin Protein Ligase E3 Component N-Recognin 5) protein is an E3 ubiquitin ligase that catalyzes the direct ubiquitination of protein substrates, most often resulting in substrate protein degradation. UBR5 is the human homolog of the Drosophilia hyperplastic discs (hyd) tumor suppressor gene. However, ubr5 is amplified and over-expressed in human ovarian and breast cancers, among others, and thought to play more of a tumor-promoting role in cancer. We previously demonstrated that targeting UBR5 expression in human ovarian cancer xenografts in mice with liposomal delivery of UBR5 siRNA inhibited tumor growth and sensitized tumors to the DNA-damaging agent cisplatin. To identify novel substrates of UBR5-stimulated degradation, we transduced OVCAR5 cells with doxycycline-inducible shRNA targeting UBR5 or a control shRNA and metabolically labelled proteins with heavy or light lysine and arginine using Stable Isotope Labeling with Amino acids in Cell culture (SILAC). Doxycycline was added for the last 48 hr and cisplatin for the last 12 hrs before cell harvest. Equal amounts of protein from both cultures were mixed, digested with trypsin and analyzed by LC-MS/MS (Orbitrap Elite MS) in three independent experiments including a label swap control. Peptides and proteins were identified and quantified using MaxQuant (FDR&amp;lt;0.01). To identify proteins differentially expressed after UBR5 knockdown, relative protein abundance was compared by two-sided t-test with permutation-based correction of the p-value. We identified multiple proteins with increased expression following UBR5 knockdown, suggesting these proteins are regulated by ubiquitin-mediated degradation by UBR5. We validated UBR5-mediated regulation of several proteins by Western blotting, including an oncogene involved in breast and ovarian cancer progression, which we further characterized. In summary, we were able to identify several novel UBR5 candidate substrates whose expression is increased following UBR5 knockdown. Further characterization of these substrates will allow us to identify novel mechanisms of UBR5 regulation of tumor progression. Citation Format: Scott T. Eblen, Jennifer R. Bethard, D Ralph Rogers, Abdelkader Daoud, Lalima K. Madan, Lauren E. Ball. Identification of novel substrates of the UBR5 E3 ubiquitin ligase in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 326.
Abstract 3246: Targeting Syk reprograms tumor-associated macrophages and enhances responses to immune checkpoint blockade and radiation therapy in high-risk neuroblastoma
Authors: Deepak Rohila, In Hwan Park, Timothy Pham, Riley Jones, Pablo Tamayo, Alice Yu, Andrew Sharabi, Shweta Joshi
Journal: Cancer Research (2023)

Abstract Neuroblastoma (NB) is the most common extracranial solid malignancy in children. As leading regulators of inflammation and tumor progression, tumor associated macrophages (TAMs) have gained major interest as immunotherapeutic targets in NB. Hence targeting or “re-educating” tumorigenic macrophages towards an immunostimulatory phenotype might improve responses to immunotherapy in this childhood cancer. Spleen tyrosine kinase (Syk) has recently been identified by our group as a novel immune-oncology target. We found that Syk is abundantly present in TAMs infiltrated in MYCN and non-MYCN amplified neuroblastoma tumors. Furthermore, genetic deletion or pharmacological inhibition of Syk markedly impaired neuroblastoma tumor growth. This effect was facilitated by macrophages that became immunogenic in the absence of Syk, skewing the suppressive tumor microenvironment towards immunostimulation and activating antitumor immune responses. Moreover, combining Syk inhibitor, R788 along with anti-PDL1 mAb and radiation provided a synergistic effect leading to complete tumor regression and durable anti-tumor immunity in aggressive MYCN-and non-MYCN-driven murine neuroblastoma tumor models. Collectively, our findings demonstrate the importance of Syk inhibitor, R788, in enhancing the anti-tumor immune responses in NB and support the clinical evaluation of R788 either alone or together with radiation and immune check point inhibitors as a potential treatment strategy for NB. Citation Format: Deepak Rohila, In Hwan Park, Timothy Pham, Riley Jones, Pablo Tamayo, Alice Yu, Andrew Sharabi, Shweta Joshi. Targeting Syk reprograms tumor-associated macrophages and enhances responses to immune checkpoint blockade and radiation therapy in high-risk neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3246.